Oncolytic viruses (OV) are viruses that specifically target and replicate in tumor cells [1]. Owing to their selectivity and oncolytic properties, OVs have generated considerable interest as an alternative or adjunct to conventional cancer therapies [2]. However, a major limitation of OV therapy is inadequate replication and propagation at the tumor site [3, 4]. Moreover, for safety reasons, many OVs are designed to be replication deficient in order to prevent them from spreading to healthy tissues, further limiting their oncolytic potential [5].
One possible solution to this problem is to supplement direct viral oncolysis with a bystander effect, in which tumor cells not directly infected by the OV will also be destroyed. This can be achieved, for example, by inserting a therapeutic or cytotoxic gene into the OV genome for delivery to the tumor site [6, 7]. Endowed with natural immunogenicity, some OVs are capable of effective stimulation of the immune system, raising the possibility of using OVs to induce an immunological anti-cancer bystander effect [8]. This idea gained further impetus with the identification [9, 10] and recent prioritization [11] of a variety of clinically relevant tumor associated antigens (TAA), which can be delivered by the OV (OV/TAA) to the tumor site [12]. In their natural state, TAAs are often poorly immunogenic [13]. However, by redirecting the anti-viral immune response towards the TAA, an immunogenic OV/TAA could potentially break this immunological tolerance. A major goal of OV research should therefore be the development of safe and effective OV/TAA agents. Sindbis virus (SV), an alphavirus with a positive single-stranded RNA genome [14], represents one of a select number of viruses that have demonstrated exceptional potential both as an OV [15, 16] and as a viral vaccine [17]. It has been previously shown that replication deficient SV vectors target and inhibit the growth of xenograft, syngeneic and spontaneous tumors in mice [16, 18].
Recently, it has also been found that SV induces the activation of natural killer (NK) cells and macrophages in tumor-bearing mice [19]. In addition, SV vectors expressing immune-modulating genes such as interleukin 12 (IL-12) have an enhanced antitumor [16] and immunostimulatory [19] effect. Nevertheless, these approaches have not generally led to complete tumor remission [19]. Moreover, some tumor cells may not be efficiently targeted by SV [20], underscoring the need to develop new ways of enhancing SV anti-cancer therapy.
Previously, it was hypothesized that the unique characteristics of SV vectors, which make them effective oncolytic agents and gene delivery systems (e.g. the ability to disseminate through the bloodstream [15] and deliver high levels of heterologous proteins [21]) could also be useful for efficient TAA delivery. Moreover, the SV life cycle, which is characterized by the absence of a DNA phase, rendering the vectors safer, also involves the production of high levels of double stranded RNA (dsRNA), a potent immunological ‘danger signal’ [22], and the subsequent activation of the type I interferon pathway [23]. The combination of safety, immunogenicity, efficient dissemination, and high TAA expression make SV/TAA an attractive OV/TAA candidate. Therefore, what is needed in the art are methods for treating mammals suffering from tumors using SV/TAA, thereby taking advantage of all of the above-mentioned benefits.